ABSTRACT / PROJECT SUMMARY There is evidence that physical activity and exercise benefit the brain, but the mechanisms for this benefit are unclear. The chronic benefits of exercise are likely a product of discreet, acute responses in exercise-related blood biomarkers and brain metabolism. This acute exercise response has not been compared in aging and Alzheimer?s Disease (AD). It is known that acute exercise elicits a powerful peripheral response in young cohorts, and exercise-related biomarkers such as glucose and lactate readily penetrate the brain. Thus, studies of these effects in aged and AD individuals are needed. It is critical to characterize and understand the acute effects of exercise, including different exercise intensities, in terms of the peripheral metabolic response and relationship with brain metabolism. This will help determine potential mechanisms for brain benefits of exercise and better inform the design of future clinical trials. Our primary goal is to characterize the acute exercise response of brain glucose metabolism and exercise-related blood biomarkers. We will characterize the brain metabolic response to an acute bout of moderate and higher intensity exercise and characterize the extent to which this differs between nondemented (ND) elderly and AD individuals. Related to this primary goal, we will quantify the peripheral biomarker response to moderate and higher intensity exercise and how this relates to brain metabolic change in both groups. We will implore a rigorous experimental design, with tightly controlled timings. We will generate a timecourse of blood draws prior to, during, and following exercise in ND and AD subjects to explore disease-related differences. We will focus on a specific exercise biomarker, lactate, but we will also characterize a wider panel of exercise-related biomarkers. We will expand on our exercise studies by leveraging a lactate clamp procedure, where we can characterize differences in lactate uptake and use (turnover) between diagnosis groups. By using stable isotopes, the lactate clamp will allow us to simultaneously examine complex dynamics of energy metabolism, such as lactate appearance, disappearance, and oxidation, and evaluate if AD subjects use this key metabolite differently. It also allows characterization of acute effects of lactate on cognition in the absence of other exercise effects. Taken together, these studies will allow us to elucidate the relationship between quantifiable blood biomarkers and brain acute response to exercise, and how exercise intensity may be important. Through in-depth characterization of these physiological responses in aging and AD, we will obtain important information regarding how relatively non-invasive outcomes, such as heart rate and blood biomarker response, relate to a key brain outcome measure (cerebral glucose metabolism). By characterizing thresholds for response of biomarkers that are needed to elicit acute brain changes, this could provide insight for the design of future long-term exercise intervention studies that are most likely to benefit the brain (i.e. moderate vs. higher intensity exercise, characteristics of participants who respond, etc) to maximize target engagement.